U.S. patent application number 12/389171 was filed with the patent office on 2009-06-18 for use of fibrous tissue inducing proteins for hernia repair.
This patent application is currently assigned to Wyeth. Invention is credited to Joanne M. Archambault, James H. Pickar, Howard Seeherman.
Application Number | 20090156462 12/389171 |
Document ID | / |
Family ID | 37024599 |
Filed Date | 2009-06-18 |
United States Patent
Application |
20090156462 |
Kind Code |
A1 |
Pickar; James H. ; et
al. |
June 18, 2009 |
USE OF FIBROUS TISSUE INDUCING PROTEINS FOR HERNIA REPAIR
Abstract
The present disclosure relates to hernia repair and methods for
stimulating growth of fascia tissue employing compositions
comprising fibrous tissue inducing proteins.
Inventors: |
Pickar; James H.;
(Springfield, PA) ; Archambault; Joanne M.;
(Arlington, MA) ; Seeherman; Howard; (Cambridge,
MA) |
Correspondence
Address: |
WYETH/FINNEGAN HENDERSON, LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
37024599 |
Appl. No.: |
12/389171 |
Filed: |
February 19, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11386749 |
Mar 23, 2006 |
|
|
|
12389171 |
|
|
|
|
60664933 |
Mar 24, 2005 |
|
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Current U.S.
Class: |
514/1.1 ;
606/151 |
Current CPC
Class: |
A61K 38/363 20130101;
A61K 38/39 20130101; A61K 38/1875 20130101; A61K 38/36 20130101;
A61L 31/047 20130101; A61K 38/37 20130101; A61K 38/57 20130101;
A61L 24/108 20130101; A61K 38/4833 20130101; A61L 31/10
20130101 |
Class at
Publication: |
514/2 ;
606/151 |
International
Class: |
A61K 38/02 20060101
A61K038/02; A61B 17/03 20060101 A61B017/03 |
Claims
1. A method of treating a fascia defect in a mammal, the method
comprising administering to a site of the fascia defect a
composition comprising a therapeutically effective amount of a
fibrous tissue inducing protein.
2. The method of claim 1, wherein the fibrous tissue inducing
protein is (1) at least 70% identical to BMP-12, BMP-13, or MP-52,
or (2) a fragment of (1) capable of inducing fibrous tissue.
3. The method of claim 1, wherein the fibrous tissue inducing
protein is BMP-12.
4. The method of claim 1, wherein the fibrous tissue inducing
protein is BMP-13.
5. The method of claim 1, wherein the fibrous tissue inducing
protein is MP-52.
6. The method of claim 1, wherein the fascia defect is associated
with a wound.
7. The method of claim 1, wherein the fascia defect is associated
with a hernia.
8. The method of claim 7, wherein the hernia is inguinal or
femoral.
9. The method of claim 1, wherein the mammal is human.
10. The method of claim 1, wherein the mammal has diabetes.
11. The method of claim 1, wherein the composition further
comprises a tissue adhesive.
12. The method of claim 11, wherein the tissue adhesive is selected
from the group consisting of fibrin, fibrinogen, thrombin,
aprotinin, Factor VIII, and 2-octyl cyanoacrylate.
13. The method claim 1, wherein the composition is delivered using
a surgical implant configured for hernia repair.
14. The method of claim 13, wherein the surgical implant comprises
a mesh.
15. The method of claim 14, wherein the mesh comprises
polypropylene, polytetrafluoroethylene, polyurethane, or
polyester.
16. The method of claim 14, wherein the mesh comprises a
bioabsorbable material.
17. The method of claim 16, wherein the bioabsorbable material is
collagen, gelatin, keratin, laminin, fibrin, fibronectin, alginate,
hyaluronic acid, polyglycolic acid, polylactic acid, polyglycolide,
or combination thereof.
18. The method of claim 13, wherein the surgical implant comprises
an anti-adhesion compound or an adhesion barrier.
19. The method of claim 18, wherein the anti-adhesion compound is
chemically modified sodium hyaluronate and carboxymethylcellulose,
or hyaluronic acid, or collagen.
20. A hernia repair device, comprising: (a) a mesh-like member
configured for repairing a fascia defect in a subject and
comprising a therapeutically effective amount of a fibrous tissue
inducing protein; and optionally (b) a means for securing the
mesh-like member to the site of the fascia.
21. The device of claim 20, wherein the fibrous tissue inducing
protein is (1) at least 70% identical to BMP-12, BMP-13, or MP-52,
or (2) a fragment of (1) capable of inducing fibrous tissue.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/386,749, filed on Mar. 23, 2006, which
claims the benefit of U.S. Patent Application No. 60/664,933, filed
on Mar. 24, 2005, both of which are herein incorporated by
reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the field of hernia repair and
other methods of strengthening or repairing the fascia tissue.
BACKGROUND OF THE INVENTION
[0003] A hernia is a fascia defect in a structure, such as, for
example, the abdominal wall, through which an organ, part of an
organ, a tissue, or part of a tissue may protrude. Usually it
involves the weakening, bulging, or actual tearing of the fascia in
a structure which normally contains an organ or tissue. There are
many types of hernias. For example, when in the lower abdominal
area, a hernia often involves intra-abdominal contents, such as the
intestines or other tissue, which pass into or through a defect in
the abdominal wall. There are at least two types of hernias that
occur in the groin region, inguinal and femoral. A femoral hernia,
which is more common in women than men, involves penetration of a
tissue or an organ through the femoral ring. Inguinal hernia
involves penetration of an organ or a tissue through the
superficial inguinal ring. An indirect inguinal hernia leaves the
abdominal cavity at the internal ring and passes down the inguinal
canal, whereas a direct hernia protrudes through the floor of the
inguinal canal in the Hesselbach's triangle. Hernias that occur in
the abdominal wall at sites other than the groin are referred to as
ventral hernias. Examples of ventral hernias include umbilical and
incisional hernias. Other types of hernias are well characterized
in surgical texts.
[0004] Known causes of hernia include obesity, pregnancy, tight
clothing, sudden physical exertion, such as weight lifting,
coughing, and abdominal injury. According to the National Center
for Health Statistics, approximately five million Americans develop
hernia each year. Inguinal hernias are more common in men,
primarily because of the unsupported space left in the groin after
the testicles descend into the scrotum. Whereas hernias in the
femoral area, at the top of the thigh, are more common in women and
commonly result from pregnancy and childbirth.
[0005] Temporary relief from the symptoms of some hernias can be
obtained by the patient wearing a truss device that applies
external pressure against the abdomen in the region of the hernia.
This well known and long-established treatment rarely, if ever,
provides more than temporary relief from pain and can result in
discomfort to the patient from wearing the device. Permanent relief
typically requires invasive surgery to return the offending organ
or tissue, if present, to its original and correct position,
followed by the repair and reinforcement of the fascia defect in
the structure which normally contains the organ or tissue.
[0006] Additionally, mesh-type patches have been used to repair
openings or holes formed in a structure through which interior
organs or tissues may protrude. Typically, these patches are
permanently implanted in a patient's body and may cause
postoperative discomfort to the patient. Further, they have been
reported to have a likelihood of harboring bacteria, thereby
leading to infections.
[0007] Although mesh-type patches are widely used for hernia
repair, recurrence is a problem frequently associated with their
use. Recurrence has been attributed, at least in part, to the
length of time required for hernia repair, which often is not met,
for example, either because the mesh-type patches are displaced
after a period of time after implantation in a patient, or they
fail to remain in the body long enough for adequate repair, such as
in the case of bioabsorbable meshes.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to methods of stimulating
growth of the fascia tissue in a subject. Fascia is a sheet or band
of fibrous connective tissue enveloping, separating, or binding
together muscles, organs, and other soft structures of the body.
Stimulation of growth of fascia tissue is important in, e.g.,
treating hernias, which often include damage to or a defect in
fascia tissue. Surgical implants and compositions described herein
are especially useful for the repair of fascia tissue defects, such
as hernias, in the abdominal cavity, including inguinal (direct and
indirect), femoral, incisional, and recurrent hernias.
[0009] Specifically, the invention provides compositions and
devices for treating a fascia tissue defect and related methods
that comprise fibrous tissue inducing proteins, e.g., members of
the bone morphogenetic protein (BMP) family such as, e.g., BMP-12,
BMP-13, or MP-52. Such compositions may further comprise a tissue
adhesive, e.g., fibrin. The use of such compositions will result in
faster and/or more effective repair of the fascia. A composition
comprising one or more fibrous tissue inducing proteins (and
optionally one or more tissue adhesives) may be delivered to the
site of a fibrous tissue defect directly or by using a surgical
implant, such as, e.g., a mesh. Alternatively, a composition
comprising one or more fibrous tissue inducing proteins and a
separate composition comprising one or more tissue adhesives may be
delivered directly to the site of a fascia tissue defect or by
using a surgical implant. Suitable fascia tissue defect repair
implants of varying sizes and shapes can be anchored to the
surrounding healthy tissue to prevent migration. Implants can also
be configured to substantially occlude and conform to the walls of
a fascia defect, e.g., in a hernia.
[0010] Methods of making and using the compositions and devices of
the invention are also provided.
DESCRIPTION OF THE EMBODIMENTS
[0011] Surgical implants, compositions, and methods described
herein generally relate to treating defects of fascia tissue, such
as, e.g., in hernia repair. More particularly, surgical implants,
compositions, and methods employ fibrous tissue inducing proteins,
e.g., members of the bone morphogenetic protein (BMP) family such
as, e.g., BMP-12, BMP-13, or MP-52. Evidence suggests that a defect
in the metabolism of collagen is involved in the pathogenesis of
certain types of hernias, such as, for example, inguinal hernia in
adults, leading to a weakening of the transversalis fascia tissue,
which poses a problem for effective repair of hernias as well as
increases the likelihood of recurrence following repair. When
fascia has been traumatized, it heals with a special type of
collagen fiber called type III. Thus, by way of theory and not as a
limitation, it is hypothesized that the fibrous tissue inducing
proteins of the inventions may contribute to correction of the
collagen metabolism, thereby treating a defect of fascia.
[0012] In general, the invention provides a method of treating a
defect of fascia tissue, comprising delivering a composition
comprising a fibrous tissue inducing protein to the site of the
fascia defect. Such compositions may further comprise a tissue
adhesive, e.g., fibrin. Compositions may be delivered to the site
of a hernia directly or by using an implantable device such as,
e.g., a surgical implant suitable for repair of a fascia tissue
defect. Surgical implants, compositions, and methods are described
in detail below.
Fibrous Tissue Inducing Proteins
[0013] Fibrous tissue inducing proteins used in the compositions,
implants, and methods of the invention are selected from the family
of proteins known as the transforming growth factors beta
(TGF-.beta.) superfamily. This family includes activins, inhibins,
and bone morphogenetic proteins (BMPs). Certain BMPs are
particularly useful in inducing fibrous tissue growth. In preferred
embodiments, the fibrous tissue inducing protein is chosen from
BMP-12, BMP-13 and MP-52 (also known as GDF-7, GDF-6, and GDF-5,
respectively), which form a subgroup of in the BMP family. The
nucleotide and protein sequences of BMP-12, BMP-13 and MP-52 are
disclosed in U.S. Pat. No. 5,658,882 and their database accession
numbers are shown in Table 1.
TABLE-US-00001 TABLE 1 Fibrous tissue inducing protein Human Mouse
BMP-12 Q7Z4P5 P43029 BMP-13 Q6KF10 P43028 MP-52 P43026 P43027
[0014] Nucleotide and protein sequences for other BMP and
TGF-.beta. family members are well known in the art.
[0015] Other candidate proteins that may be useful in repair of
fascia tissue defects can also be identified using one or more
assays described herein to evaluate hernia repair, for example, by
measuring the tissue integration strength in the presence of a
candidate protein, or by measuring collagen (especially collagen
type III) section by cell in vitro or in vivo. BMP-13 and MP-52 are
86% identical to each other, and 80% identical to BMP-12, whereas
they are only 57% identical to next most homologous member of the
TGF-.beta. superfamily, BMP-2 (See, e.g., FIG. 4 of U.S. Pat. No.
6,096,506). Thus, it is expected that a protein that is a least
about 70% identical to any one of BMP-12, BMP-13 and MP-52 would
possess the required fibrous tissue inducing activity. Accordingly,
some embodiments include the use of a fibrous tissue inducing
protein that is, for example, 70%, 75%, 80%, 85%, 90%, 95%, 98%,
99% identical to BMP-12, BMP-13 or MP-52. Such proteins can be
engineered, for example, by mutating or deleting a number of
non-conserved amino acid residues, for example, those residues that
differ between the corresponding mouse and human sequences (or
other species) and or those residues that differ between any two of
BMP-12, BMP-13, and MP-52, when sequences are aligned. Conservative
amino acid substitutions in native sequences are also contemplated.
Alternatively, fragments of such homologous or modified proteins,
as well as fragments of native fibrous tissue inducing proteins,
that retain fibrous tissue inducing activity may be used in the
methods of the invention.
[0016] Fibrous tissue inducing proteins may either be recombinantly
produced or be purified from natural sources. In the preferred
embodiments, the proteins are of the human origin and are
recombinant. Methods for recombinant product of proteins are well
known and are described, for example, in U.S. Pat. No.
5,658,882.
[0017] In some embodiments, an effective amount of a fibrous tissue
inducing protein that may be used in the compositions and implants
described herein is that amount which is sufficient for repairing
fascia in a subject at a rate that is 10%, 20%, 30%, 50% faster or
more than the corresponding repair in the absence of the fibrous
tissue inducing protein and will generally depend upon the size and
nature of the fascia defect being repaired and/or the surface area
of the implant being employed. In other embodiments, an effective
amount of a fibrous tissue inducing protein is that amount which is
sufficient for stimulating fascia tissue growth at a rate that is
10%, 20%, 30%, 50% faster or more than the growth in absence of the
fibrous tissue inducing protein.
[0018] Generally, the amount of protein used for repairing a fascia
defect and/or for stimulating growth of fascia tissue is in a range
of from 0.001 to 10 mg, 0.01 to 1 mg, or 0.1 to 0.5 mg per cubic
centimeter of material required. In some instances, dosages may be
deduced from the concentration of protein in the composition
applied to the mesh. For example, a composition applied to the mesh
may contain from 0.001 to 10 mg/ml, from 0.01 to 1.0 mg/ml, or from
0.1 to 0.5 mg/ml of one or more fibrous tissue inducing proteins.
For example, if a mesh has a 1 cc volume and can absorb an equal
amount of liquid, 1 ml of composition is applied to the mesh, for a
soak load of 100%. Soak loads can vary from 25% to 200%, from 50%
to 150%, or from 75% to 100%. Particular dosage will be determined
by the clinical indication being addressed, as well as by various
patient variables (e.g., weight, age, sex) and clinical
presentation (e.g., extent of and/or site of the fascia defect,
etc.).
Tissue Adhesives
[0019] Tissue adhesives for use in the compositions and surgical
implants of the invention include fibrin, fibrinogen, thrombin,
aprotinin, and Factor VIII. Commercially available tissue adhesives
include TISSEEL.RTM. (fibrinogen; Baxter Healthcare Corp.,
Deerfield, Ill.) and DERMABOND.TM. (2-octyl cyanoacrylate; Ethicon,
Somerville, N.J.). These adhesives may be combined directly with a
fibrous tissue inducing protein or applied to the site of a fascia
defect either before, after, or at the same time as the fibrous
tissue inducing protein. The adhesives may also be incorporated
into a surgical implant in the same ways as described for the
fibrous tissue inducing proteins. Compositions including tissue
adhesives can also be used for stimulating growth of fascia tissue.
In some embodiments, tissue adhesives, alone or in combination with
at least one fibrous tissue inducing protein, are delivered in a
composition in the form of a paste or a gel.
Other Additives
[0020] Additives that may be useful in the compositions and
surgical implants described herein, include, without limitation,
pharmaceutically acceptable salts, polysaccharides, peptides,
proteins, amino acids, synthetic polymers, natural polymers, and/or
surfactants. Additives which help in reducing or preventing the
adhesion of surrounding tissue and organs to the surgical implant
are particularly useful and are referred to herein as anti-adhesion
compounds. Non-limiting examples of such additives include, for
example, chemically modified sodium hyaluronate and
carboxymethylcellulose (modified with the activating agent
1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC)
and available commercially as SEPRAFILM.RTM. adhesion barrier
(Genzyme Corp., Cambridge, Mass.)), hyaluronic acid, and
collagen.
[0021] In some embodiments, compositions and surgical implants
described herein contain an antimicrobiotic agent, such as an
antibiotic. Administration of antibiotics serves to prevent
infections. Examples of antibiotics that may be used include, but
are not limited to, TYGACIL.RTM. (tigecycline; Wyeth, Madison,
N.J.), cephalosporins such as cephazolin and cephamandol,
netilmycin, penicillins such as oxacillin or mezlocillin,
tetracycline, metronidazole or aminoglycosides such as gentamycin
or neomycin, and rifampicin. Generally, the amount of antibiotic
used is in a range of from 0.001 to 10 mg, 0.01 to 1 mg, or 0.1 to
0.5 mg per cubic centimeter of material required.
[0022] Like the adhesives, these additives may be combined directly
with the fibrous tissue inducing protein, or applied to the site of
a fascia defect either before, after, or at the same time as the
fibrous tissue inducing protein. The additives may also be
incorporated into a surgical implant, in the same ways as described
for the fibrous tissue inducing proteins.
[0023] Compositions useful in the methods of the invention may be
delivered directly to a site of fascia defect. They may be applied
(e.g., injected) to the site, while the defect is otherwise
repaired using traditional surgical techniques. The compositions
may also be used in conjunction with a surgical implant that has
not been treated with such a composition. Alternatively,
compositions described herein may be applied to the affected area
either before or after a surgical implant is put into place.
Surgical Implants
[0024] Surgical implants for hernia repair typically include a
mesh, or other means of structural support. An implant has a
structure that may serve to both release the protein in a
time-dependent manner and provide structural support for hernia
repair. The surgical implant may comprise at least one fibrous
tissue inducing protein and, optionally, at least one tissue
adhesive. The surgical implant can be treated by any method, so
long as the method allows the fibrous tissue inducing protein(s) to
be delivered to the site of a fascia defect in a subject. For
example, a mesh may be coated with a fibrous tissue inducing
protein by immersing or soaking it in a solution of fibrous tissue
inducing protein(s), for example, from 1 minute to 1 hour, 10
minutes to 45 minutes, or 15 minutes to 30 minutes. Coating may be
also achieved by, for example, spraying the mesh with such a
solution. In yet other embodiments, a mesh may be impregnated with
a fibrous tissue inducing protein by the use of chemical
cross-linking.
[0025] Meshes that can be employed as surgical implants include,
for example, polypropylene mesh (PPM) which has been used
extensively in hernia repair to provide the necessary strength and
support for tissue growth for the repair of abdominal defects in
hernia. Other examples include expanded polytetraflouroethylene
(ePTFE), sepramesh biosurgical composite, polyethylene
terephthalate (PET), and titanium. Ideal mesh properties include,
without limitation, inertness, resistance to infection at the site
where the mesh is implanted, molecular permeability, pliability,
transparency, mechanical integrity and strength, and
biocompatibility.
[0026] Implants may have a dorsal surface and a visceral surface.
The dorsal surface is the portion of the implant which faces
outward away from a fascia defect and the visceral surface is the
portion which faces inward towards the defect. Prior to
implantation, some of the implants described herein may, in an
unstressed state, assume a flat or planar shape, or may assume a
concave and/or convex shape on one or more surfaces.
[0027] In yet other embodiments, an implant comprises a mesh in the
form of a sponge, for example, which is soaked or immersed in a
composition comprising a fibrous tissue inducing protein and
optionally a tissue adhesive, so that the composition fully
permeates the pores of the sponge. Such a sponge can either be made
from a synthetic material, such as polyvinyl alcohol, or from a
bioabsorbable material, such as collagen, gelatin, keratin,
laminin, fibrin, or fibronectin. Examples include HELISTAT.RTM.,
HELITENE.RTM., and VITAGUARD.RTM. (Integra Life Sciences,
Plainsboro, N.J.), and ULTRAFOAM.RTM. (Davol, Inc., Cranston,
R.I.). In certain instances, it is preferable to use a
bioabsorbable sponge that is only temporarily present in the body
of a subject. Meshes and sponges described herein may also be
referred to by other terms, such as for example, a pad or a gauze,
etc.
[0028] In some embodiments, implants may be sufficiently flexible
to allow a surgeon to manipulate the implant to conform to the
surgical site and/or ease delivery during a laparoscopic procedure.
However, in some circumstances, a stiffer arrangement that limits
compression and/or expansion of the implant may be preferred. In
certain embodiments, an implant may be collapsible, such as by
folding, rolling, or otherwise, into a slender configuration, so
that it may be delivered through a narrow lumen of a laparascopic
device. Flexibility of the implant is influenced by many factors,
including, the materials from which the implant is made, treatments
applied to the implant or any other features of the body of the
implant.
[0029] A mesh implant may either include a single mesh or be formed
from two or more mesh segments that are joined or overlap. In some
embodiments, meshes are configured to continuously deliver at least
one fibrous tissue inducing protein and optionally at least one
tissue adhesive at the site of a fascia defect in a subject,
thereby resulting in repair of the defect. It is contemplated that
meshes can be configured to deliver at least one fibrous tissue
inducing protein continuously, for example, for approximately 15
days, 20 days and 30 days. The length of time, however, will vary
depending on the extent and site of the defect to repair, age of
the patient and other clinical parameters that are typically taken
into consideration by surgeons.
[0030] Surgical implants for use in the methods of the invention
may be manufactured, sterilized, and contained in packages until
opened for use in a surgical procedure. Any appropriate
sterilization process can be used, including the conventional
physical or chemical methods or treatment with ionizing radiation
such as, for example, gamma or beta rays.
Delivery Methods
[0031] Surgical implants and compositions described herein can be
used in any of the surgical procedures that are used by surgeons
for repair of a fascia tissue defect. In some embodiments, an
incision is made at the site of a hernia in a subject and a
surgical implant described herein is inserted to cover the area of
the defect. In other embodiments, a laparoscopic method is used to
deploy a surgical implant in the patient. Fascia tissue defect
repair may be performed using general, regional, or local
anesthesia. Some of the advantages of local anesthesia include a
short recovery time and ability to test the repair
intra-operatively. Further, local anesthesia avoids the respiratory
and immune depressive effects of general anesthesia.
[0032] As previously noted, compositions described herein may be
applied directly to the site of a fascia defect, injected at the
site of the defect, or applied to a surgical implant before or
after it is placed at the site of the fascia defect. In some
embodiments, compositions described herein may be used in
conjunction with a mesh which covers a fascia defect in a structure
which normally contains an organ or a tissue, such as, for example,
the abdominal wall. For example, compositions comprising a fibrous
tissue inducing protein and optionally a tissue adhesive may be
delivered to the site of a hernia using a device, suitable for
administering the composition to or near the site of the hernia.
Such a method of delivery would eliminate the need to treat or soak
a mesh, or other surgical implant, in the composition prior to its
implantation in a subject.
[0033] Various methods of hernia repair and implants suitable for
use in hernia repair are known and described, for example, in U.S.
Pat. Nos. 5,176,692; 5,569,273; 6,800,0825,824,082; 6,166,286;
5,290,217; and 5,356,432. Generally, such devices include (a) a
mesh-like member configured for repairing a fascia defect in a
subject; and optionally (b) a means for securing the mesh-like
member to the site of the fascia. The devices of the invention are
distinct in that the surgical implant or mesh-like member contains
a therapeutically effective amount of one or more fibrous tissue
inducing proteins and optionally, one or more tissue adhesives.
Uses
[0034] Compositions and surgical implants described herein may be
tested in a wide variety of well known and available animal models
for repair of fascia tissue defects. For example, the strength of
hernia repair can be tested according to porcine groin hernia
repair stress-loading tests taught in Uen, "Comparative
Laparoscopic Evaluation of the PROLENE polypropylene hernia system
vs. the PerFix plug repair in a porcine groin hernia repair model,"
J. Laparoendosc. Adv. Surg. Tech. 14(6):368-73 (2004). Light
microscopy can also be used to evaluate the health of other
structures near a hernia, as taught in Berndsen et al., "Does mesh
implantation affect the spermatic cord structures after inguinal
hernia surgery? An experimental study in rats," Eur. Surg. Res.
36(5):318-22 (2004).
[0035] Is contemplated that in addition to repairing hernias and
stimulating growth of fascia tissue, the methods of the invention
may also be applied to repairing damage to fascia tissue associated
with, for example, colon surgery, rectal surgery, plastic surgery,
trauma, surgery, vascular surgery, pelvic floor repair, or a wound,
as well as fascia defects caused by chronic strain and
immobility.
[0036] Accordingly, this invention may be used to treat various
types of fascia defects, including for example, serious hernias,
recurrent hernias, hernias in patients with diabetes or other
conditions that are associated with impaired wound healing, or any
other fascia defects in patients with diabetes or other conditions
that are associated with impaired wound healing.
[0037] The following examples are illustrative of the present
invention and are not limiting in any manner. Modifications,
variations and minor enhancements are contemplated and are within
the scope of the present invention.
EXAMPLES
[0038] The following materials and methods were used in the
subsequent Examples. It will be appreciated by those of skill in
the art that while the Examples employ BMP-12, they can be
performed in a similar manner with BMP-13, MP-52, or any another
fibrous tissue inducing protein. Similarly, other tissue adhesives
and surgical implants may be substituted for those described in the
Examples.
[0039] Various meshes employed as surgical implants in the
following Examples include the Bard mesh which is a polypropylene
mesh (PPM) and the Bard Composix mesh, which has two layers of PPM
and a layer of expanded polytetraflouroethylene to minimize tissue
adhesion to the mesh (Davol, Inc., Cranston, R.I.).
[0040] Additionally, the sepramesh biosurgical composite (Genzyme
Surgical Products, Cambridge, Mass.) is also used, which includes
PPM coated with chemically modified sodium
hyaluronate/carboxymethylcellulose (HA/CMC). Examples of
bioabsorbable meshes that may be used in the surgical implants
described herein include the polyglactin vicryl mesh (Ethicon,
Somerville, N.J.).
[0041] Various bioabsorbable sponges that may be employed as
surgical implants include collagen sponges HELISTAT.RTM.,
HELITENE.RTM. and VITAGUARD.RTM. (Integra Life Sciences,
Plainsboro, N.J.), and ULTRAFOAM.RTM. (Davol, Inc., Cranston,
R.I.).
[0042] Finally, the tissue adhesive TISSEEL.RTM. (Baxter Healthcare
Corp., Deerfield, Ill.) is used to prepare a composition comprising
TISSEEL.RTM. and rhBMP-12.
[0043] A. Preparation of Surgical Implants for Use in Hernia
Repair
[0044] It is understood that any of the meshes and/or sponges that
are currently available can be used as surgical implants. In the
case of a mesh, the mesh is either coated with a composition
including at least one fibrous tissue inducing protein, e.g.,
rhBMP-12, or it is impregnated with a composition comprising at
least one fibrous tissue inducing protein.
[0045] Each of Bard mesh, Bard composix mesh, sepramesh biosurgical
composite and the polyglactin vicryl mesh, following receipt from
the manufacturer, are coated with a composition including rhBMP-12.
Either both surfaces of the mesh or only one surface may be coated,
such as the surface that faces outward from the defect after
implantation, i.e., the dorsal surface. Additionally, the meshes
are coated with an antibiotic to prevent infections in the area
where the meshes are implanted. A suitable antibiotic can either be
included in the same composition as the fibrous tissue inducing
protein or it can be coated separately onto the mesh.
[0046] In some instances, the meshes are impregnated with a
composition including a fibrous tissue inducing protein, e.g.,
rhBMP-12. This is achieved by cross-linking the fibrous tissue
inducing protein to the fibers of the mesh before the fibers are
interwoven into a mesh. However, it is expected that there will be
no difference in hernia repair whether the meshes are coated or
impregnated with a fibrous tissue inducing protein.
[0047] The sponges used in the surgical implant are either soaked
in a composition including at least one fibrous tissue inducing
protein or at least one fibrous tissue inducing protein can be
cross-linked to the sponge material, for example, collagen.
Cross-linking may be achieved using any suitable cross-linking
agent.
[0048] B. Generation of an Animal Model for Hernia
[0049] An animal model for hernia is generated as follows. The
guidelines for the animal study are in accordance with the NIH
guidelines described in Guide for the Care of Laboratory Animals.
(National Academy Press, 1996). Mature female New Zealand white
rabbits (Oryctolagus cuniculuc), each weighing about 3.5-4.5 kg,
are preanesthetized with acepromazine (0.5 mg/kg, sc). Ten to
thirty minutes after administering the preanesthetic, animals are
anesthetized with ketamine hydrochloride (30 mg/kg, im) and
xylazine hydrochloride (10 mg/kg, im). The animals are intubated
and fully anesthetized with isoflurane (1.0-3.0%) and oxygen
(1.5-2.0 liters/min) followed by administration of buprenorphine
(0.02-0.05 mg/kg, sc) as an analgesic.
[0050] The abdomen of each animal is shaved and prepped with a
povidone/iodine scrub and successive alcohol wipes. A 10 to 12 cm
skin incision is made beginning approximately 2 cm caudal to the
xyphoid process and a 5 to 7 cm full-thickness muscular peritoneal
abdominal wall defect is created by excising a segment around the
linea alba. If necessary, the arteries are clamped for hemostatsis.
The cecum of the animals is externalized from the abdominal cavity
and abraded with a sterile nylon surgeon's brush. The cecum is
visually divided into four sections and each section is abraded
with 15 strokes such that punctate bleeding develops. The cecum is
subsequently returned to the abdominal cavity and the animals are
ready for implantation of a surgical implant and fibrous tissue
inducing protein composition.
[0051] C. Histology
[0052] To evaluate fascia defect repair, the entire tissue area
surrounding the original defect from each of the animal groups is
excised and fixed in 4% paraformaldehyde (Polysciences, Warrington,
Pa.) in PBS. The tissue specimens are embedded in paraffin and 5
.mu.m thick sections are cut and stained with hematoxylin and
eosin, and subject to a blind analysis. Morphologic
characterization of cellular responses and tissue ingrowth is noted
for each of the meshes.
[0053] D. Tissue Integration Strength Assay
[0054] A tissue integration assay is used to assess the strength of
the tissue following hernia repair using the various methods
described herein. Strips about 2.times.5 cm are cut parallel to the
transverse axis of an implant, which includes the implant, the
tissue/implant interface as well as normal tissue following
recovery of the animals. The tensile strength of each tissue sample
is measured using a tensiometer using a load cell. The maximum load
at which the tissue/implant interface fails for each sample is
recorded.
Example 1
A Mesh Coated with a Composition Containing a Fibrous Tissue
Inducing Protein Designed for More Effective and Stronger Hernia
Repair in an Animal Model
[0055] Rabbits are prepared as described above and are divided into
two groups for each of the meshes: Bard mesh; Bard composix mesh
and the sepramesh biosurgical composite. In each case, one group is
implanted with the mesh prehydrated in sterile saline the other
group is implanted with the mesh coated with a composition
including a fibrous tissue inducing protein, rhBMP-12, as described
above.
[0056] In each case, the mesh is secured to the 5.times.7 cm defect
margin created as described above, with 3-0 Prolene in a simple
continuous pattern. The subcutaneous tissue is closed with
absorbable suture in a continuous subcuticular pattern. The animals
are exuberated and allowed to recover in an incubator. In each of
the six groups (i.e., Bard mesh and Bard mesh+rhBMP; Bard composix
mesh and Bard composix mesh+rhBMP-12; and sepramesh biosurgical
composite and sepramesh biosurgical composite+rhBMP-12), some of
the animals are euthanized at about 15 days, some of the animals
are euthanized at about 20 days and others are euthanized at
approximately one-month after the surgery to monitor the overall
performance of the treated and untreated meshes over time. The
repair of the abdominal defect in each group is evaluated using the
histological protocol and the tissue integration strength assays
described above.
[0057] In each of the groups, it is predicted that the hernia
repair will be stronger in the animal group which is implanted with
the mesh coated with rhBMP-12, relative to the animals which are
implanted with the meshes alone.
Example 2
A Surgical Implant Treated with a Composition Containing a Fibrous
Tissue Inducing Protein Designed for Faster Repair of Hernia in an
Animal Model
[0058] Rabbits are prepared as discussed above, and are divided
into two groups. One group of rabbits is implanted with a PPM mesh
and the other group of rabbits is implanted with a bioabsorbable
sponge. Specifically, in one group, a hernia defect is covered with
a PPM mesh coated with a composition including a fibrous tissue
inducing protein, e.g., rhBMP-12, or a hernia defect is covered
with a PPM mesh treated with a sterile saline solution, as
discussed above. In the second group or rabbits, a hernia defect is
either covered using a collagen sponge immersed in a composition
including a fibrous tissue inducing protein, e.g., rhBMP-12, or it
is covered with the sponge immersed in a sterile saline
solution.
[0059] In each group of animals, the surgical implant, i.e., PPM
mesh or the bioabsorbable sponge is secured to the 5.times.7 cm
defect margin created using the method described above. The animals
are allowed to recover and some of the animals from each group are
euthanized at approximately one-month to evaluate the hernia
repair.
[0060] In each of the groups, it is predicted that the hernia
repair will be faster in the animal group which is implanted with
the mesh coated with rhBMP-12, relative to the animals which are
implanted with the meshes alone.
Example 3
A Composition Comprising BMP-12 and a Tissue Adhesive Designed to
be Effective Alone or when Coated on a Mesh
[0061] Rabbits are prepared as described above and are divided into
three groups: mesh alone, composition comprising rhBMP-12 and
TISSEEL.RTM., and the composition comprising rhBMP-12 and
TISSEEL.RTM. applied to the mesh.
[0062] In the groups with a mesh, the mesh is secured to the
5.times.7 cm defect margin created as described above, with 3-0
Prolene in a simple continuous pattern. The subcutaneous tissue is
closed with absorbable suture in a continuous subcuticular pattern.
The animals are exuberated and allowed to recover in an
incubator.
[0063] In the group with a composition comprising rhBMP-12 and
TISSEEL.RTM., the hernia is repaired surgically as described above
and the rhBMP-12 and TISSEEL.RTM. composition is injected at the
site of the hernia. The subcutaneous tissue is closed with
absorbable suture in a continuous subcuticular pattern. The animals
are exuberated and allowed to recover in an incubator.
[0064] In each of the three groups, some of the animals are
euthanized at about 15 days, some of the animals are euthanized at
about 20 days and others are euthanized at approximately one-month
after the surgery to monitor the overall performance of the
treatments over time. The repair of the abdominal defect in each
group is evaluated using the histological protocol and the tissue
integration strength assays described above.
[0065] It is predicted that the hernia repair will be faster in the
animal group which is implanted with the mesh coated with rhBMP-12
and TISSEEL.RTM., followed by the composition containing rhBMP-12
and TISSEEL.RTM., relative to the animals which are implanted with
the mesh alone.
[0066] The specification is most thoroughly understood in light of
the teachings of the references cited within the specification
which are hereby incorporated by reference. The embodiments within
the specification provide an illustration of embodiments of the
invention and should not be construed to limit the scope of the
invention. The skilled artisan readily recognizes that many other
embodiments are encompassed by this specification. All
publications, patents, and sequences cited are incorporated by
reference in their entirety. To the extent the material
incorporated by reference contradicts or is inconsistent with the
present specification, the present specification will supercede any
such material. The citation of any references herein is not an
admission that such references are prior art.
[0067] Unless otherwise indicated, all numbers expressing
quantities of ingredients, treatment conditions, and so forth used
in the specification, including claims, are to be understood as
being modified in all instances by the term "about." Accordingly,
unless otherwise indicated to the contrary, the numerical
parameters are approximations and may very depending upon the
desired properties sought to be obtained. Unless otherwise
indicated, the term "at least" preceding a series of elements is to
be understood to refer to every element in the series. Those
skilled in the art will recognize, or be able to ascertain using no
more than routine experimentation, many equivalents to the specific
embodiments described herein. Such equivalents are intended to be
encompassed by the following claims.
* * * * *